Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition
Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition
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苯甲酸衍生物NC-5抗甲型流感病毒活性及其神经氨酸酶抑制作用
DOI：
10.3390/ijms20246261
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Zhou, Changlin
中科院分区：
文献类型：
--
作者：
Guo, Min;Ni, Jiawei;Zhou, Changlin
目前可用的抗甲型流感病毒的药物主要靶向神经氨酸酶（NA）或基质蛋白2（M2）离子通道。抗药性病毒的出现需要开发新的抗病毒化学物质。我们的研究应用基于细胞的方法来评估一系列新合成的苯甲酸衍生物和4-（2，2-二（羟甲基）-5-氧代吡咯烷-1-基）-3-（5-环己基-4H-1，2，4-三唑-3-基）氨基）的抗病毒活性。被称为NC-5的苯甲酸被发现具有抗病毒活性。NC-5对甲型流感病毒A/FM/1/47（H1N1）、A/Beijing/32/92（H3 N2）和奥司他韦耐药突变体A/FM/1/47-H275 Y（H1N1-H275 Y）的抑制作用呈剂量依赖性。对H1N1和H1N1-H275 Y的半数有效浓度（EC 50）分别为33.6 μM和32.8 μM，表明NC-5在耐药病毒感染中较奥司他韦有较大优势。NC-5的50%细胞毒性浓度（CC 50）大于640 μM。经口给予NC-5可保护感染H1N1和H1N1-H275 Y的小鼠，在100 mg/kg/d剂量下分别获得80%和60%的存活率，减轻体重减轻，并减轻病毒诱导的肺损伤。NC-5可抑制病毒生物合成后期NP和M1蛋白的表达水平，抑制NA活性，从而影响病毒的释放。我们的研究证明NC-5在体内和体外都具有有效的抗流感病毒活性，这意味着它可以被视为治疗流感病毒感染的有希望的候选药物，包括奥司他韦耐药病毒。
The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.